Despite long-term investment, influenza continues to be a significant worldwide problem. Influenza A viruses (IAV) are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S. and 40 million people worldwide. Pandemics in 1957 and 1968, while less severe, were also of major public health importance. A novel influenza A virus of swine origin became pandemic in 2009, causing the first pandemic in 41 years. In addition, annual epidemic influenza cases are also very significant resulting in up to 49,000 deaths in the U.S. annually. Human volunteer influenza virus challenge studies are being performed at the NIH Clinical Center using both a 2009 influenza A/H1N1 virus and a 2012 influenza A/H3N2 virus under FDA-approved INDs. A healthy volunteer screening study continued at the Clinical Center to identify patients who will qualify and be available for current and future challenge studies. A human volunteer influenza virus challenge study evaluating correlates of protection against the 2009 influenza A/H1N1 virus was completed this year. The cornerstone of protection remains vaccination, and approved vaccines seek to elicit a hemagglutination inhibition (HAI) titer of 1:40 as the primary correlate of protection. However, recent poor vaccine performance raises questions regarding the protection afforded and whether other correlates of protection should be targeted. A healthy volunteer challenge study was performed with a wild-type 2009 A(H1N1)pdm influenza A challenge virus at the NIH Clinical Center to evaluate two groups of participants with HAI titers of 1:40 and <1:40. The primary objective was to determine whether participants with HAI titers of 1:40 were less likely to develop mild to moderate influenza disease (MMID) after intranasal inoculation. HAI titers of 1:40 were protective against MMID but did not reduce the incidence of symptoms alone. Although the baseline HAI titer correlated with some reduction in disease severity measures, overall, the baseline NAI titer correlated more significantly with all disease severity metrics and had a stronger independent effect on outcome. This study demonstrated the importance of examining other immunological correlates of protection rather than solely HAI titers. This challenge study confirmed the importance of NAI titer as a correlate and for the first time established that it can be an independent predictor of reduction of all aspects of influenza disease. This suggests that NAI titer may play a more significant role than previously thought and that neuraminidase immunity should be considered when studying susceptibility after vaccination and as a critical target in future influenza vaccine platforms. In addition to this multiple clinical studies have been ongoing during the past year. These include a phase II study of a monoclonal influenza A stalk antibody therapy in our H1N1pdm challenge model under a CRADA with Crucell/Johnson and Johnson. We have completed enrollment for a clinical study of zoonotic infections in children exhibiting swine at Ohio state fairs, and we also initiated two new clinical studies including a dose finding validation study of a seasonal H3N2 challenge virus and a long term study of influenza immunity in those who have participated in influenza challenge studies. In addition to these studies we continue to produce new challenge viruses including newer seasonal influenza A viruses as well as Influenza B viruses, and have initiated collaborations with Rockefellar University, Stanford, FDA, and within NIAID to further study human influenza infection and how it relates to other viral infections. Lastly we have finalized a CRADA and developed a protocol to perform a phase I study of a universal mosquito bourn disease vaccine in response to the current Zika outbreak.